The giant wave that marks the beginning of the end — the neurobiology of dying

The human brain is highly sensitive to oxygen deprivation. Extensive and irreversible damage occurs within approximately 10 minutes of cardiac (and hence circulatory) arrest. For the first time, researchers from Charité – Universitätsmedizin Berlin and the University of Cincinnati have been able to study these events in humans. The results from this research, which has been published in Annals of Neurology*, may inform future treatment strategies of cardiac arrest and stroke.

Oxygen deprivation results in brain injury. For years, researchers have been studying the underlying processes in animals: within 20 to 40 seconds, the brain enters an 'energy-saving mode' – it becomes electrically inactive, and all interneuronal communication ceases. Within a few minutes, the brain's fuel reserves have become depleted that maintain the uneven distribution of ions between the inside and outside of nerve cells, and the ion gradients start to break down. This breakdown takes the form of a massive wave of electrochemical energy release in the form of heat, which is known as 'spreading depolarization'. More vividly described as a 'brain tsunami', this energy loss spreads through the cortex and other areas of the brain, triggering pathophysiological cascades which gradually poison the nerve cells. Importantly, this wave remains reversible up to a certain point in time: nerve cells will recover fully if circulation is restored before this point is reached. However, if circulation remains disrupted, the cells will die. Until now, recordings of electrical brain activity obtained from human subjects have been of limited applicability, and experts have been divided as to the transferability of results from animal-based research.

It is usually impossible to take the relevant measurements in the minutes immediately following a stroke or cardiac arrest. Under the leadership of Prof. Dr. Jens Dreier of Charité's Center for Stroke Research, and working with Prof. Jed Hartings of the Mayfield Clinic in Cincinnati, researchers have now been able to study such cases for the first time. Their research was facilitated by a very specific setup. Specialist neuromonitoring techniques, which enable the early detection and subsequent treatment of clinical complications, are becoming an increasingly common feature of modern neurocritical care. In particular, electrocorticography and invasive methods of monitoring oxygen are becoming increasingly significant. In contrast to conventional electroencephalography, electrocorticography goes beyond the process of recording epileptic seizure activity, enabling clinicians to record spreading depolarization with never-before-seen precision. Over the past few years, a number of international clinical studies have been able to confirm that, in many severe cases of acute brain injury, spreading depolarizations develop as soon as the patient's condition worsens. When this happens, treatment must target the underlying causes of this phenomenon, in order to limit its occurrence.

As part of their observational study, the researchers used state-of-the-art neuromonitoring technology. Scientific analysis of both monitoring data and each patient's clinical course showed that the event known as 'terminal spreading depolarization' also occurs in humans, beginning within minutes of circulatory arrest. "We were able to show that terminal spreading depolarization is similar in humans and animals. Unfortunately, the research community has been ignoring this essential process of central nervous system injury for decades, all because of the mistaken assumption that it does not occur in humans," explains Prof. Dreier. The reasons for this have been primarily methodological in nature. Reestablishing circulation as rapidly as possible has, until now, been the sole aim of treatment in stroke and cardiac arrest patients. "Knowledge of the processes involved in spreading depolarization is fundamental to the development of additional treatment strategies aimed at prolonging the survival of nerve cells when brain perfusion is disrupted," explains Prof. Dreier. He adds: "This of course follows from the tenet espoused by Max Planck that insight must precede application; our insights can give us hope for the future."